Is hemochromatosis a risk factor for Alzheimer's disease?

Connor, James R.; Milward, Elizabeth A.; Moalem, Sharon; Sampietro, Maurizio; Boyer, Philip J.; Percy, Maire E.; Vergani, Carlo; Scott, Rodney J.; Chorney, Michael J.

doi:10.3233/jad-2001-3506

Cited by 73 publications

(45 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Iron overload has been postulated to play a role in the pathogenesis of various neurodegenerative diseases such as Parkinson's disease [12], Alzheimer's disease [13,14], and amyotrophic lateral sclerosis [15]. This suggests that the central nervous system is susceptible to iron-induced oxidative damage.…”

Section: Introductionmentioning

confidence: 99%

Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe

Gnana-Prakasam

Martin

Mysona

et al. 2008

Biochemical Journal

View full text Add to dashboard Cite

SummaryHepcidin is a hormone central to the regulation of iron homeostasis in the body. It is believed to be produced exclusively by the liver. Ferroportin, an iron exporter, is the receptor for hepcidin. This transporter/receptor is expressed in Müller cells, photoreceptor cells, and retinal pigment epithelium (RPE) within the retina. Since the retina is protected by the retinal-blood barriers, we asked whether ferroportin in the retina is regulated by hepcidin in the circulation or whether the retina produces hepcidin for regulation of its own iron homeostasis. Here we show that hepcidin is expressed robustly in Müller cells, photoreceptor cells, and RPE, closely resembling the expression pattern of ferroportin. We also show that bacterial lipopolysaccharide (LPS) is a regulator of hepcidin expression in Müller cells and RPE, both in vitro and in vivo, and that the regulation occurs at the transcriptional level. The action of LPS on hepcidin expression is mediated by the Toll-like receptor-4. The upregulation of hepcidin by LPS occurs independent of Hfe (Human leukocyte antigen-like protein involved in Fe homeostasis). The increase in hepcidin levels in retinal cells in response to LPS treatment is associated with a decrease in ferroportin levels. The LPS-induced upregulation of hepcidin and consequent downregulation of ferroportin is associated with increased oxidative stress and apoptosis within the retina in vivo. We conclude that retinal iron homeostasis may be regulated in an autonomous manner by hepcidin generated within the retina and that chronic bacterial infection/inflammation of the retina may disrupt iron homeostasis and retinal function.

show abstract

Section: Introductionmentioning

confidence: 99%

Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe

Gnana-Prakasam

Martin

Mysona

et al. 2008

Biochemical Journal

View full text Add to dashboard Cite

show abstract

“…Zinc, iron, and copper are significantly elevated in AD pathology (140)(141)(142)(143)(144). Histochemical analysis of AD brain reveals the presence of nonenzymatic redox activity that appears to represent copper as well as iron (145).…”

Section: Role Of Oxidative Stress In Admentioning

confidence: 99%

Oxidative Stress and Neurotoxicity

Sayre

Perry

Smith

2007

Chem. Res. Toxicol.

743

494

View full text Add to dashboard Cite

There is increasing awareness of the ubiquitous role of oxidative stress in neurodegenerative disease states. A continuing challenge is to be able to distinguish between oxidative changes that occur early in the disease from those that are secondary manifestations of neuronal degeneration. This perspective highlights the role of oxidative stress in Alzheimer's, Parkinson's, and Huntington's diseases, amyotrophic lateral sclerosis, and multiple sclerosis, neurodegenerative and neuroinflammatory disorders where there is evidence for a primary contribution of oxidative stress in neuronal death, as opposed to other diseases where oxidative stress more likely plays a secondary or by-stander role. We begin with a brief review of the biochemistry of oxidative stress as it relates to mechanisms that lead to cell death, and why the central nervous system is particularly susceptible to such mechanisms. Following a review of oxidative stress involvement in individual disease states, some conclusions are provided as to what further research should hope to accomplish in the field.

show abstract

“…Iron is an important cause of oxidative stress in AD because it is found in considerable amounts in the AD brain [45] and, as a transition metal, is involved in the formation of · OH via the Fenton reaction [46]. Furthermore, it has been reported that amyloid-β itself is a substrate for · OH [44]. Amyloid-β extracted from postmortem AD brains presents oxidative modifications such as carbonyl adduct formation, histidine loss, and dityrosine cross-linking, making this protein less water soluble and less susceptible to degradation by the proteases [44,47,48].…”

Section: Redox-active Metalsmentioning

confidence: 99%

“…In patients with AD, overaccumulation of iron in the hippocampus, cerebral cortex, and basal nucleus of Meynert colocalizes with AD lesions, senile plaques, and NFT [27,44]. Iron is an important cause of oxidative stress in AD because it is found in considerable amounts in the AD brain [45] and, as a transition metal, is involved in the formation of · OH via the Fenton reaction [46].…”

Section: Redox-active Metalsmentioning

confidence: 99%

“…Furthermore, it has been reported that amyloid-β itself is a substrate for · OH [44]. Amyloid-β extracted from postmortem AD brains presents oxidative modifications such as carbonyl adduct formation, histidine loss, and dityrosine cross-linking, making this protein less water soluble and less susceptible to degradation by the proteases [44,47,48]. Furthermore, it has been reported that amyloid-β deposition and AβPP cleavage and synthesis are promoted by the presence of iron [49], likely consequential of oxidative stress-mediated events [50,51].…”

Section: Redox-active Metalsmentioning

confidence: 99%

See 1 more Smart Citation

Nucleic acid oxidation in Alzheimer disease

Moreira

Nunomura

Nakamura

et al. 2008

Free Radical Biology and Medicine

187

113

View full text Add to dashboard Cite

Increasing evidence suggests that oxidative stress is intimately associated with Alzheimer disease pathophysiology. Nucleic acids (nuclear DNA, mitochondrial DNA, and RNA) are one of the several cellular macromolecules damaged by reactive oxygen species, particularly the hydroxyl radical. Because neurons are irreplaceable and survive as long as the organism does, they need elaborate defense mechanisms to ensure their longevity. In Alzheimer disease, however, an accumulation of nucleic acid oxidation is observed, indicating an increased level of oxidative stress and/or a decreased capacity to repair the nucleic acid damage. In this review, we present data supporting the notion that mitochondrial and metal abnormalities are key sources of oxidative stress in Alzheimer disease. Furthermore, we outline the mechanisms of nucleic acid oxidation and repair. Finally, evidence showing the occurrence of nucleic acid oxidation in Alzheimer disease will be discussed.

show abstract

Is hemochromatosis a risk factor for Alzheimer's disease?

Cited by 73 publications

References 21 publications

Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe

Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe

Oxidative Stress and Neurotoxicity

Nucleic acid oxidation in Alzheimer disease

Contact Info

Product

Resources

About